The tumor suppressor p53 has been implicated as playing a key role in human cancer. p53 exerts much of its activity as a transcription factor that regulates gene expression that contributes to the suppression of tumor formation. Its C-terminus bears remarkable similarity to that of histone tails. Both are highly enriched in basic amino acids and both are extensively post-translationally modified. Like histone tails, the C-terminus of p53 can be considered a protein-protein interaction module. This in turn regulates its activity as a transcription factor. To address the role of the C-terminus of p53 in its activity, a targeted mutation was made in the mouse that leads to endogenous expression of a truncated form of p53 that lacks the C-terminal 24 amino acids. When p53?CTD is expressed in the germ-line, mice show two overt phenotypes: a reduced number of hematopoietic stem cells leading to severe anemia and impaired proliferation of granule cells resulting in defective cerebellar development and ataxia. The underlying molecular basis involves tissue-specific alterations in p53 target gene selection and expression. The striking tissue specificity of these phenotypes was unexpected and quite intriguing. In addition, study of the Trp53?CTD/?CTD mice has led to the identification of novel, tissue-specific p53 target genes. Given that p53 has such potent tumor suppressor activity, it is intriguing to speculate that this might be exploited as a rational basis for targeted therapy. However, the apparently ubiquitous expression of p53 suggests that it would be difficult to achieve an effective therapeutic index. Findings with Trp53?CTD/?CTD mice demonstrate that the C-terminal domain of p53 exerts tissue- specific effects in a target gene-selective manner. It is thus proposed that interfering with the function of the C- terminal domain of p53 can be utilized for targeted therapy that is highly tumor-specific. With that long-term goal in mind, three specific aims are proposed. The first is to elucidate the molecular basis for the C-terminal domain in p53-mediated bone marrow failure. Second is to determine the role of the p53 C-terminal domain in cerebellar granule cell homeostasis and tumorigenesis. Finally, is to gain molecular insight into how the p53 C- terminal domain regulates activated p53 signaling. As the C-terminus has been well characterized as a protein- protein interaction module, it is proposed that inhibiting the protein interactions of the C-terminus represents a novel targeted therapy in specific tumor types. Thus, the long-term goal of these studies is to use in vivo mouse models to gain novel insights into the role of p53 in leukemia and medulloblastoma, as well as to provide new approaches for targeted therapies in these diseases.